JAK belongs to a family of tyrosine kinases that are involved in inflammation, autoimmune diseases, proliferative diseases, transplant rejection, diseases involving impairment of cartilage turnover, congenital cartilage malformations and/or diseases associated with hypersecretion of IL6. The present invention also provides methods for the production of the compounds, pharmaceutical compositions comprising the compounds, methods for the prophylaxis and/or treatment of diseases involving inflammation, autoimmune diseases, proliferative diseases, transplant rejection, diseases involving impairment of cartilage turnover, congenital cartilage malformations and/or diseases associated with hypersecretion of IL6 by administering a compound of the present invention.
Janus kinases (JAK) are cytoplasmic tyrosine kinases that transduce cytokine signaling from membrane receptors to STAT transcription factors. Four JAK family members are described in the prior art: JAK1, JAK2, JAK3 and TYK2. Upon binding of the cytokine to its receptor, JAK family members auto- and/or transphosphorylate each other, followed by phosphorylation of STATs and then migrate to the nucleus to modulate transcription. JAK-STAT intracellular signal transduction is suitable for the interferons, most interleukins, as well as a variety of cytokines and endocrine factors such as EPO, TPO, GH, OSM, LIF, CNTF, GM-CSF and PRL (Vainchenker W. et al. (2008)).
The combination of genetic models and small molecule JAK inhibitor research revealed the therapeutic potential of several JAKs. JAK2 gene mutation research is one of the breakthrough progress of hematological research in recent years. Myeloproliferative diseases (MPD) are disclosed in the prior art, including polycythemia vela (PV), essential thrombocythemia (ET) and idiopathicmyelofibrosis (IMF), which are malignant diseases caused by the lesions of a group of hematopoietic stem cell lesion. A JAK2 point mutation (JAK2V617F) in this group of diseases was discovered by the researchers in 2005, which led to a new era in MPD diagnosis and treatment. JAK2V617 is a point mutation that occurs at exon v617 at exon 14, and valine (V) is substituted by phenylalanine (F). In the structure of JAK2, JH1 is the kinase domain; and Va1617 is located in JH2 adjacent to JH1, which is a pseudokinase domain, binds to JH1 and inhibits its activation. V617F mutations cause JH2 to lose inhibitory effect on JH1 kinase activity, leading to sustained activation of JAK2, resulting in enhanced cell proliferation [Kilpivaara 0, Levine R L. JAK2 and MPL mutations in myeloprolifer-ative neoplasms: discovery and science. Leukemia. 2008; 22(10):1813-7]. There is a high incidence of JAK2V617F mutation in patients with polycythaemia vera, essential thrombocythaemia, and idiopathic myelofibrosis. It was determined by Allele-Specific PCR that, the incidence of JAK2V617F mutation in patients with polycythaemia vera was 90%; in patients with essential thrombocythaemia and idiopathic myelofibrosis was 50%-60% [Baxter E J, Scott L M, Campbell P J, et al. Lancet. 2005; 365 (9464): 1054-61]. The molecular basis of these diseases without finding JAK2 mutation in patients lacking of V617F mutation is unclear. In 2007, an exon 12 mutation was found in JAK2V617F-negative MPD patients. This mutation can also cause JH2 to lose inhibitory effect on JH kinase activity, which provides molecular markers and genetic mechanisms for JAK2V617F-negative patients with myeloproliferative diseases [Scott L M, Tong W, Levine R L, et al. JAK2 exon 12 mutations in polycythemia vera and idiopathic erythrocytosis. N Engl J Med 2007; 356:459-68-]. In normal physiological conditions, JAK2 mediates signal transduction of various cytokines, including erythropoietin (EPO), thrombopoietin (TPO), granulocyte-macrophage colony stimulating factor, interleukin-3 and growth factor, and regulates and promotes cell proliferation. JAK2 gene plays an important role in adjustment of hematopoietic, and its downstream STAT family is a family of proteins that bind to DNA. The STAT family couples with JAK phosphorylated signaling pathway (JAK-STAT signaling pathway) and play a role in the regulation of transcription. JAK-STAT can directly correlate extracellular signals with gene expression regulation, initiate transcription and expression of responsive genes, complete the signal transduction process of cytokine receptors such as erythropoietin receptor (EPOR) and thrombopoietin receptor (MPL/TPOR), resulting in cell proliferation effects.
Tofacitinib is a pan jak inhibitor, a non-highly specific JAK2 inhibitor, its structural formula is as follows:
